Method and apparatus for continuous flow microwave-assisted chemistry techniques

ABSTRACT

The invention is a method and associated instrument for microwave assisted chemistry. The invention includes the steps of directing a continuous flow of fluid through a microwave cavity while applying microwave radiation to the cavity and to the continuous flow of materials therein, monitoring the pressure of the fluid in the cavity; and cooling the fluid in the cavity when the pressure exceeds a predetermined setpoint pressure.

RELATED APPLICATIONS

This invention is a divisional of co-pending application Ser. No.10/064,623, filed Jul. 31, 2002, and is related to commonly assigned andco-pending application Ser. No. 10/126,838, filed Apr. 19, 2002; andissued U.S. Pat. No. 6,744,024, issued Jun. 1, 2004; U.S. Pat. No.6,649,889, issued Nov. 18, 2003; U.S. Pat. No. 6,630,652, issued Oct. 7,2003; and U.S. Pat. No. 6,753,517, issued Jun. 22, 2004. Theseapplications are incorporated entirely herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to methods and apparatus formicrowave-assisted chemistry techniques, and in particular to the use ofmicrowaves in organic synthesis reactions. Most chemical reactions aregenerated, initiated, or accelerated by increasing temperature inaccordance with relatively well-understood rate and thermodynamicprinciples. Accordingly, because microwaves can produce heat in certainqualifying substances, microwaves have been used to generate heat in awide variety of chemical and chemistry related processes and techniques.These have typically included microwave drying for loss-on-dryingmoisture content analysis, and digestion of samples as a preparationstep prior to other analytical techniques such as atomic absorptionspectroscopy on the digested residues.

The carefully controlled conditions required for organic synthesis,however, generally have been unsuited (or vice versa) for use in typicalearlier-generation microwave laboratory equipment. Specifically,although microwave devices can produce relatively large amounts ofpower, the nature of microwave cavities and the wavelength of microwavestend to produce varying levels of power within the three dimensionalspace defined by the cavity. For large samples or samples where of hightemperature effects are required or desired, this aspect of microwaveheating does not matter and indeed permits microwaves to work betterthan most other types of heating for such purposes.

Chemical synthesis, however, and in particular organic synthesis,requires a more careful and to some extent delicate application of heatto chemical reactions. In response to the need for more carefullyapplied microwave energy for organic synthesis purposes (by way ofexample and not limitation), a number of newer devices have beendeveloped which accomplish this purpose. The apparatus and instrumentset forth in the above co-pending applications are exemplary of such adevice, which has gained rapid acceptance as a method for carrying outorganic synthesis using microwaves. The instrument is also commerciallyavailable under the DISCOVER™ trademark of CEM Corporation, Matthews,N.C., the assignee of the present invention. The success of theDISCOVER™ instrument has led to an increase in the use of microwavesynthesis techniques, and the corresponding need for additional methodsof carrying out synthetic reactions in this advantageous manner.

First, in order to scale up reactions from the laboratory bench top touseful synthesis of larger amounts, it is generally advantageous to usecontinuous rather than batch systems. Certain reactions are also carriedout more advantageously in a flowing condition because of the nature ofthe catalysts used. As another issue, microwave penetration of materialstends to be effective, but spatially limited; i.e., microwaves tend topenetrate part of a sample, but no further. This spatial limitation canprevent optimum utilization of microwave power in a batch content.Stated differently, the lack of penetration depth can prevent microwaveirradiation from affecting an entire batch sample with the result thatinterior portions of the sample are merely conductively orconvectionally heated by the exterior portions.

Accordingly, a flow-through system that allows greater penetration byexposing a smaller volume to microwaves at any given time can beadvantageous. Yet other reactions (e.g., esterification to producepolyesters) will move to an equilibrium condition, unless one of thereaction products is removed. In the case of the esterification reactionthat produces polyester, water is removed in order to prevent anequilibrium from being established between the reactives and theproducts, thus encouraging the production of the finished esterifiedpolyester, rather than an equilibrium mixture of reactants and products.Continuous flow reactors can be advantageous in accomplishing suchreactions.

Continuous flow reactors can also help reduce the total forces (usuallypressure) that can build up in batch reactions because a proportionallysmaller volume is irradiated at any given time. Additionally, the speedwith which microwaves interact with responsive materials (essentiallyinstantaneously) makes flow-through techniques at reasonable ratesfeasible in situations where conventional heating would be too slow tobe effective.

Microwaves are generally defined as those waves falling in the portionof the electromagnetic spectrum having frequencies of from about 300 to300,000 megahertz (MHz). The corresponding wavelengths are on the orderof between about one centimeter and one meter. These are of coursearbitrary limits and will be understood as such. Most common instrumentsthat incorporate microwave radiation use a preferred assigned frequencyof 2450 megahertz.

As understood by those familiar with chemical reactions exposed tomicrowaves, the energy of microwave photons is relatively low comparedto the typical energies of chemical bonds (80-120 Kcal/mole).Accordingly microwaves do not directly affect molecular structure, butinstead tend to generate molecular rotations, and by the resultingkinetic energy typically generates heat. Microwave heating does not,however, depend on the thermal conductivity of the materials beingheated, and thus offers an additional advantage over typical conductionheating methods.

Because of the speed with which microwaves can heat materials, thetemperature of the sample (reactants, starting materials, etc.) canquickly increase beyond a desired or advantageous temperature.Accordingly, another desired aspect of a chemistry synthesis instrument,including a microwave-assisted instrument, is the capability ofcontrolling temperature while a reaction proceeds. Lack of temperaturecontrol can produce a number of undesired consequences. First, thetemperature may increase to a point at which the reactives or theproducts decompose rather than react properly. Secondly, if there arevolatile products being generated by the reaction, which is typical inmany organic synthesis reactions, the increased pressure must becontained or released. Alternatively, the increased pressure can changethe reaction kinetics in an undesired manner. Finally, an increase intemperature can also produce physical consequences to the reactionvessels and the instrument itself should pressures and temperatures andpressures become so high as to create some sort of unintended mechanicalor physical failure.

Temperature control is available for microwave instruments. For example,commonly assigned U.S. Pat. No. 6,227,041 illustrates how measuring thetemperature of a sample can be used to moderate (typically reducing) theapplied microwave power, and thus prevent a sample from overheating anddecomposing.

All chemical reactions are driven by thermodynamic factors, and most areinitiated when energy is added to the reactants. In many cases,microwave irradiation can apply energy to chemical reactants faster andmore efficiently than conventional heating steps. Accordingly, when themicrowave power is reduced or stopped in an effort to controltemperature, the efficiency of the reaction can be reduced even as heatis being produced. Thus a reaction proceeding at an elevated temperaturein the absence of microwaves can still be proceeding less-efficientlythan it would if microwaves were being applied.

Accordingly, commonly assigned application Ser. No. 10/064,261, filedJun. 26, 2002, now U.S. Pat. No. 6,744,024, discloses an instrument formicrowave synthesis that incorporates proactive cooling in a single-modemicrowave cavity. By moderating the heat generated by the appliedmicrowaves or the reaction itself, the instrument permits a greateramount of microwave power to be applied to the reaction as may bedesired or necessary.

The instrument described in the '261 application is, however, abatch-type instrument rather than a continuous-flow device.

The general attraction of continuous flow chemistry is generally wellunderstood in concept, and a number of attempts have been made to carryit out. For example, in commonly assigned U.S. Pat. No. 5,215,715, asample is moved in the form of a slug on a continuous basis through amicrowave heated digesting system. The same or similar system is used incommonly assigned U.S. Pat. No. No. 5,420,039. Other recent workincludes U.S. Pat. No. 6,242,723 in which two separate sets of reactantscan be moved into a vessel where they can react while remainingseparated by an appropriate filter while being irradiated withmicrowaves. U.S. Pat. No. 6,316,759 discloses an apparatus forconducting gas chromatography while heating the columns usingmicrowaves. U.S. Pat. No. 6,303,005 shows a distillation system thatuses microwave heating. U.S. Pat. No. 5,672,316 shows a semi-flowthrough technique that has certain proactive temperature controls, thegoal of the technique being to maintain a pressure equilibrium inhigh-pressure reactions. U.S. Pat. No. 5,382,414 shows a reaction vesselthat includes a flow-through passage for use in a conventional microwavecavity.

U.S. Pat. No. 5,387,397 shows a flow-through system that merelyincorporates a “microwave enclosure” or a “suitable cavity” rather thana single mode cavity. The '397 patent also incorporates apost-irradiation cooling element. The '397 patent thus fails torecognize the power density issues raised by conventional multi-modecavities and likewise fails to recognize that the act of reducingmicrowave power to control temperature can correspondingly reduce theefficient progress (rate and yield) of certain chemical reactions.

In the scientific literature, several attempts have been carried outusing a conventional microwave oven (rather than a specific instrument)in which a fixed bed reactor is placed in the cavity and exposed tomicrowaves as the reactants flow there through. These include Plazl,AIChE Journal Volume 43, Number 3, March 1997 and Pipus, ChemicalEngineering Journal 76 (2000) 239-245. Other flow-through techniqueshave used conventional cavities as well including reports by Braun,Microporous and Mesoporous Materials 23 (1998) 79-81 and Chemat, Journalof Microwave Power and Electromagnetic Energy, Volume 33, No. 2, 1998,pages 88-94.

All of these, however, use the more typical large microwave cavity thatapplies large amounts of power, but at a low and spatially inconsistentpower density in the manner discussed above, thus making successfulflow-through techniques less likely and less reproducible.

Accordingly, there remains a need for a more elegant solution to theproblem of conducting sensitive organic reactions at controlledtemperatures while maximizing the available use of microwave energy in adesirable manner.

SUMMARY OF THE INVENTION

The invention is a method of microwave-assisted chemistry comprisingdirecting a continuous flow of fluid through a microwave cavity whileapplying microwave radiation to the cavity and to the continuous flow ofmaterials therein. The method includes monitoring the pressure of thefluid in the cavity and cooling the fluid in the cavity when thepressure exceeds a predetermined set pressure. In related aspects, thepressure measurement can be used to moderate the applied power, or atemperature measurement can be used to moderate the cooling or theapplied power.

In another aspect, the invention is a method of microwave-assistedchemistry that includes the steps of carrying out a chemical reaction inbatch format while irradiating the reactants with microwave radiationand while concurrently externally cooling the reaction vessel to therebyidentify an optimum power level and reaction time and without exceedinga temperature at which the reactants decompose or otherwise actdifferently than desired. The method thereafter includes the steps ofdirecting a continuous flow of corresponding reactants through a singlemode microwave cavity while applying microwave radiation to the cavityand to the continuous flow of materials therein at the power level andreaction time identified during batch format reaction of the samecorresponding reactants. The method then comprises and concurrentlyincludes externally cooling the flowing reactants while applying themicrowave radiation in order to continue at the identified power levelwhile avoiding an undesired increase in the temperature of the reactionand the reactants.

In yet another aspect, the method comprises directing a continuous flowof fluid through a single mode microwave cavity while applying microwaveradiation to the cavity and to the continuous flow of materials thereinand then purifying the reaction products with a scavenging composition,including scavenging combined with microwave irradiation.

In another aspect, the invention includes a method of microwave-assistedchemistry comprising the steps of directing a continuous flow of fluidthrough a single mode microwave cavity while applying microwaveradiation to the cavity and to the continuous flow of materials therein.In the next step, the invention comprises directing the fluid from thecavity to a spectroscopic flow cell and spectroscopically evaluating thefluid, and then moderating the conditions in the cavity in response tothe spectroscopic evaluation.

In its apparatus aspects, the invention comprises an instrument formicrowave-assisted chemistry that includes a microwave cavity, a flowcell in the cavity, a pump for directing fluid reactants from at leastone source to the flow cell, a pressure meter in fluid communicationwith the flow cell for measuring the pressure of fluid in the flow celland a cooling system for cooling the flow cell in the cavity.

In another aspect, the instrument includes a microwave cavity, a flowcell in the cavity, a pump in fluid communication with the input side ofthe flow cell for directing fluids from a source and into the flow cellin the cavity, a spectroscopy cell external to the cavity and in fluidcommunication with the output side of the flow cell, and a spectrometerwith the spectroscopy cell in the optical path of the spectrometer foranalyzing the characteristics of the fluid flowing from the flow celland through the spectroscopy cell.

In yet another aspect, the apparatus of the invention comprises amicrowave cavity, an attenuator releasably engaged with the cavity andin microwave communication with the cavity, and a flow cell releasablyengaged with the attenuator in a manner that fixes the positions of theattenuator and the flow cell with respect to one another when they areengaged and that correspondingly fixes the flow cell in the sameposition with respect to the cavity when the attenuator is engaged withthe cavity.

The foregoing and other objects and advantages of the invention and themanner in which the same are accomplished will become clearer based onthe followed detailed description taken in conjunction with theaccompanying drawings in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an instrument used in accordance withthe present invention.

FIG. 2 is a perspective view of elements of an instrument according tothe present invention including a magnetron, cavity, and attenuator.

FIG. 3 is a cross sectional view of the cavity and attenuator of FIG. 2.

FIG. 4 is a partially exploded view of the cavity, attenuator and flowcell according to the present invention.

FIG. 5 is an exploded perspective view of portions of the attenuator andflow cell of the present invention.

FIG. 6 is a perspective view of the flow cell and attenuator of thepresent invention.

FIG. 7 is a side elevational view of the flow cell and attenuator ofFIG. 6.

FIG. 8 is a cross sectional view of the attenuator and flow celldemonstrated in FIGS. 6 and 7.

FIG. 9 is another cross sectional view of selected elements of the flowcell and attenuator.

FIG. 10 is a schematic diagram of one embodiment of the instrument ofthe invention.

FIG. 11 is a schematic diagram illustrating another embodiment of thepresent invention.

FIGS. 12 through 16 are chemical equations for exemplary reactionschemes for which the present invention has been found useful.

DETAILED DESCRIPTION

The invention is a method of microwave-assisted chemistry comprisingdirecting a continuous flow of fluid through a microwave cavity whileapplying microwave radiation to the cavity, and to the continuous flowof materials therein. In the most preferred embodiments, the methodcomprises directing the continuous flow of fluid through a single-modemicrowave cavity. The nature of microwave radiation and single modes isgenerally well understood in this art, and discussions can be found innumerous sources, including the previously incorporated patents andapplications.

The invention further comprises monitoring the pressure of the fluid inthe cavity. The pressure of the fluid is determined by several factors,including the pumping and flow rate, but in many circumstances,particularly organic synthesis, as reaction temperatures increase, andas reaction products are generated, potentially including gases, thepressure within a closed system will increase. Accordingly, monitoringthe pressure of the fluid is one method of monitoring the progress of anongoing chemical reaction.

In response to, or in addition to, the monitoring of the pressure, themethod of the invention comprises cooling the fluid in the cavity whenthe pressure exceeds a pre-determined set point pressure. The coolingstep preferably comprises circulating or directing a coolant into andthrough the cavity in response to the pressure set point determination,with air being a satisfactory and preferred coolant under manycircumstances. If desired, however, the step of cooling the fluid cancomprise circulating a different fluid as may be convenient ornecessary. In the most preferred embodiments, and as will be discussedwith respect to the drawings and the apparatus aspects of the invention,the steps of directing and cooling the fluid comprise directing thefluid through a tube and then externally cooling the tube, preferablywith a cooling fluid such as air, nitrogen, including nitrogen generatedfrom liquid nitrogen, carbon dioxide, or any other appropriate gas thatotherwise does not interfere with the reaction or the apparatus.

The proactive cooling step of the invention permits continued highenergy transfer using the microwave irradiation, while minimizing oreliminating potentially undesired temperature-driven effects. Using theinvention, very high temperatures can be reached in a “point” or“instantaneous” sense that help drive the reaction more efficiently, butare rarely reflected in the bulk temperature of the reactants.

It will also be understood that the cooling step is not limited to asimple on-or-off context. In addition, the cooling step can includeincreasing or decreasing the rate of cooling at any given time inresponse to the measured parameters.

In preferred embodiments, the steps of monitoring and cooling the fluidcomprise sending a signal representative of the pressure from a pressuremonitor or detector, to a processor; i.e., a semiconductor device withboth memory and logic functions. The method then includes using theprocessor to compare the monitored pressure to the set point pressure,and then sending a signal from the processor that initiates and runs acavity cooling device whenever the monitored pressure exceeds the setpoint pressure.

In another aspect, the step of directing the fluid can comprisedirecting the fluid in the presence of another non-reacting material,the most common of which are catalysts. Because the catalyst is beingused in the presence of microwave radiation, it (and its support in somecases) can be selected to couple with microwaves (if desired) or to betransparent to microwaves (again, if so desired).

In another aspect, the invention is a method of microwave assistedchemistry comprising carrying out a chemical reaction in batch formatwhile irradiating the reactants with microwave radiation and whileconcurrently externally cooling the reaction vessel to thereby identifyan optimum power level for the reaction and without exceeding atemperature at which the reactants decompose or otherwise sufferheat-related consequences different from those desired or intended. Theterm “reactants” is used herein in its generally understood sense torefer to those compounds or elements which react in a chemical reactionto form different compounds and elements. Nevertheless, it will beunderstood by those of skill in the art that the reaction can also becarried out in the presence of other materials such as reagents orcatalysts while still operating within the scope of the invention.

In the present invention, once the optimum power is identified that canbe applied in the presence of the available cooling, the methodcomprises directing a continuous flow of corresponding reactants;—i.e.,not the same samples, but the same chemical compositions—through asingle mode microwave cavity while applying microwave radiation to thecavity and to the continuous flow of materials therein at the powerlevel identified during the batch format reaction of the same reactants.The method includes the step of cooling the flowing reactants,preferably by externally cooling the tubing through which the fluidflows in the cavity while applying the microwave radiation in order tocontinue at the identified and selected power level while avoiding anundesired increase in the temperature of the reaction or an undesiredeffect upon the reactants.

In another aspect, the invention is a method of microwave-assistedchemistry that comprises directing a continuous flow of fluid through asingle-mode microwave cavity while applying microwave radiation to thecavity and to the continuous flow of materials therein, and thenpurifying the reaction products with a scavenging composition. Inpreferred embodiments, the scavenging step comprises directing the fluidthrough a column (or any equivalent or other satisfactory device) filledwith a solid support that includes a scavenging functional groupselected from the group consisting of electrophilic scavengers,nucleophilic scavengers, and combinations thereof. These terms are wellunderstood in the art and appropriate scavengers are commerciallyavailable from a number of suppliers. In many cases, the scavenger is amicroporous resin or a silica gel that supports a desired functionalgroup. For example, a macroporous aminomethylpolystyrene resin orequivalent silica gel is suitable for a scavenger of acids or acidchlorides. In another example, a benzaldehyde-based scavenger is usefulfor scavenging primary amines or hydrazines and hydroxylamines. As athird example (and the selection is almost endless), macroporous resinthat includes a polymer-bound ethylenediamine is useful for scavengingacids, acid chlorides, anhydrides and other electrophilic compounds. Asimilar set of scavenging compounds can be selected for nucleophilicscavenging, and combinations can be used where appropriate. By way ofexample and not limitation, such macroporous scavenger resins areavailable from Polymer Laboratories (Amherst, Mass.) under theStratoSpheres trademark, and scavengers based in silica gel (which arepresently preferred to date) are available from SiliCycle Inc. of QuebecCity, Canada. Other exemplary scavengers are available fromCalbiochem-Novabiochem Corporation of San Diego, Calif., or fromSigma-Aldrich Corporation, St. Louis, Mo.

The scavenging step can remove unwanted byproducts from the reactionleading to a purified product, which, in turn, can be immediatelydirected to a separation step, preferably a chromatography separationstep and most preferably a high pressure liquid chromatographyseparation step. High pressure liquid chromatography is well understoodin the art and will not be otherwise discussed herein and those ofordinary skill in this art will be able to couple HPLC to the methodsteps in this manner without undue experimentation.

As in the previous embodiments, the method can also comprise monitoringthe pressure of the fluid in the cavity and cooling the fluid when thepressure exceeds a predetermined setpoint. The temperature can also bemonitored, for example, of the fluid, the ambient air in the cavity, orthe external temperature of the tubing, whatever is desired ornecessary, in the cavity and then the cavity can be cooled by a coolingsystem when the temperature exceeds a pre-determined setpoint.

In another aspect, the invention is a method of microwave-assistedchemistry that comprises directing a continuous flow of fluid through asingle-mode microwave cavity while applying microwave radiation to thecavity and to the continuous flow of materials therein, and thendirecting the fluid from the cavity to a spectroscopic flow cell andspectroscopically evaluating the fluid, and then moderating theconditions in the cavity in response to the spectroscopic evaluation.The step of directing the fluid to a spectroscopic flow cell preferablycomprises directing it to an in-line cell, but can also comprisedirecting the fluid to a sample line separate from a main line and thenevaluating the fluid in the sample line.

In preferred embodiments, the spectroscopy step is selected from thegroup consisting of ultraviolet, infrared, and Raman spectroscopy.Although it will be understood that the invention is not limited tothese types of spectroscopy, these are quite exemplary foridentification of particular molecules and compounds. As is wellunderstood by those of ordinary skill in this art, a typicalspectrometer includes a source and detector. The source directselectromagnetic radiation within a particular frequency range throughthe sample and then to the detector. The difference between the lightemitted by the source and that collected by the detector is known as theabsorbance, and the absorbance at particular frequencies identifiesparticular characteristics of elements and compounds. In particular,ultraviolet spectroscopy identifies electronic transitions withinmolecules and identifies them on that basis. Infrared spectroscopymeasures asymmetric vibrational movements in molecules and identifiesthem correspondently, while Raman spectroscopy identifies compounds bytheir symmetric vibrational modes. Each of these techniques is wellunderstood in the relevant art and need not be discussed in detailherein, and can be used in conjunction with the other elements of theinvention by those of ordinary skill in this art and without undueexperimentation. Furthermore, because in most circumstances the identityand nature of the reactants, the desired products, and the potentialbyproducts are well understood, each of these spectroscopy techniquescan be extremely useful in quickly identifying such products andbyproducts and potentially unreactive starting materials.

The immediate spectroscopic evaluation of the products from thecontinuous flow provides an excellent in-line monitoring capabilitybecause the conditions in the cavity can be quickly monitored based onthe evaluations of the spectrometer. As in the previous embodiments, thepreferred moderating step is to cool the cavity in response to anundesired rise in temperature which is or may be reflected by thespectroscopic results. Alternatively, the moderation can compriseadjusting the fluid flow rate through the cavity, or moderating themicrowave power applied in the cavity.

In any of the embodiments of the invention, when a moderation of themicrowave power is desired or necessary, a preferred technique is thatset forth in commonly assigned U.S. Pat. No. 6,084,226, which explains apreferred technique for applying and adjusting continuous power in amicrowave context. As set forth therein and elsewhere, the word“continuous” refers to the application of microwave power in short dutycycles so that the most efficient power level can be applied using theshortest duty cycle possible.

There are a number of method aspects of the invention and these are bestunderstood with respect to the accompanying drawings.

FIG. 1 is a perspective view of an instrument according to the presentinvention and broadly designated at 20. A first portion of theinstrument broadly designated at 21 is a single mode focused microwavedevice essentially identical to the devices described and claimed incommonly assigned and co-pending application Ser. No. ______. The singlemode cavity device 21 incorporates and integrates a modular pumpingsystem broadly designated at 22. The nature of the modular system issuch that any number of pumps can be included, and thus any number ofdifferent reactants can be included in a given reaction scheme. Innormal circumstances, between one and four pumps will be incorporated,but in each case they will be identical in concept and operation tothose discussed with respect to these particular illustrations. Thepumps can be any standard pump suitable for handling the reactants (andsolvents or reagents) and producing the desired flow rates (e.g., 1-5ml/min). Pumps suitable for high-pressure liquid chromatography (HPLC)are suitable for the present invention, with pumps from ScientificSystems, Inc. (State College, Pa.), being incorporated in the presentlypreferred embodiments.

The instrument 20 includes a microwave cavity in the interior portionsof the instrument, and thus not entirely visible in FIG. 1, but has itslocation designated at 23 in FIG. 1. A flow cell (FIGS. 3-8), is presentin the cavity 23. The pumps are similarly not visible in the perspectiveview of FIG. 1, but are carried within the pump housings 24, which, asnoted above, are modular in structure and execution.

FIG. 1 does, however, illustrate the pump heads at 25 into which liquidflows from any appropriate source vessel. These can be customizedvessels, or beakers, or Erlenmeyer flasks, or any other appropriatepiece of laboratory glassware, or can comprise the flow from the outputof another reactor or instrument. The pump outlets are illustrated at 26and are likewise conventional in that they typically need to match toappropriate chemically inert tubing for the reactants. Each pumppreferably also includes a priming and purging valve 27.

The tubing used to carry the reactants into the cavity 23 is omitted forthe sake of clarity from FIG. 1, but are generally directed into anappropriate opening illustrated at 30 in FIG. 1. FIG. 1 also shows theattenuator portion 31 of the instrument 20, which, in a manner wellunderstood in this art, prevents microwaves in the cavity frompropagating outside of the instrument.

The various reactants exiting from the pump outlets are initially mixedat the T-fitting 32 which preferably also includes an appropriate filterand a relatively tortuous flow path in order to encourage the reactantsto blend prior to their entry into the cavity.

Other details illustrated in FIG. 1 include a nut 33 that helps fix aportion of the attenuator 31 and flow cell together in a manner bestunderstood with respect to the remainder of the drawings. A respectivecontrol panel 34 acts as the input/output device for each pump andincludes appropriate data entry keys as well as a variety of indicators,both light emitting diodes (LEDs) and liquid crystal displays (LCDs)that display the status or operation of the instrument 20. A similardisplay 35 forms a portion of the single mode cavity portion 21 of theinstrument 20.

FIG. 2 is a perspective view of portions of the instrument 20 in theabsence of the housing illustrated in FIG. 1. Several of the elementsare common with FIG. 1, including the cavity 23, which can now be seenas circular in shape, the attenuator 31, the inlet and outlet opening 30for the reactant fluid tubes (not shown), and the nut 33 on theattenuator 31. Additionally, FIG. 2 illustrates that the instrumentincludes a microwave source 37, which in most circumstances is amagnetron, but can also comprise a klystron, or a solid-state device,such as a Gunn diode. The magnetron 37 is in microwave communicationwith the cavity 23, typically and preferably through the wave-guide 40.The interior of the cavity is preferably the single mode designincorporating a plurality of openings from the wave-guide, as set forthin the previously incorporated applications.

The attenuator 31 is releasably engageable with and from the cavity 23for removing and replacing the vessel (in this case the flow cell) fromthe cavity 23. Typically, the attenuator engages with a ¼-turn design,best illustrated in other drawings, and FIG. 2 illustrates the handles41 that help facilitate this task.

In preferred embodiments, the cooling system of the invention isprovided by a flow of air into the cavity, it having been foundconvenient, appropriate, and satisfactory to use air in mostcircumstances. As noted earlier, however, other gases (noble gases, CO₂,N₂) including gases that have been cooled, can be used as well.Accordingly, FIG. 2 shows the airflow inlet 42 and an airflow solenoidvalve 43. Because the valve 43 is a standard on and off device, theinstrument typically, additionally includes an airflow regulator 44 thatcan variably control the flow of air to the cavity. FIG. 2 illustrates asection of tubing 45 for the airflow between the solenoid and theregulator, and also from the regulator to the cavity 23.

In preferred embodiments, the instrument includes a processor (104 inFIGS. 10 and 11) in communication with a pressure sensor 108 (FIG. 10)and the cooling system represented by the air regulator 44 and tubing 45for moderating the cooling of the flow cell (not visible in FIG. 2) inthe cavity 23, in response to the pressure measured by the pressuresensor 108. As in the case of the pumps, the pressure sensor can be thesame as or similar to those conventionally used in HPLC, and suchpressure sensors are available from many of the same manufacturers thatprovide the HPLC pumps and related equipment and components.

Although the processor is not shown in FIG. 2, an appropriate set ofplugs 46 are illustrated, and show the relative position of theprocessor and its accompanying board in this particular embodiment.Additionally, FIG. 2 illustrates the cabling 47 that provides the signalcommunication between and among the processor, the air flow regulator44, any appropriate temperature measuring device and the power supplyfor the magnetron 37, all of which can be used to moderate theconditions in the cavity. With the processor in communication with thesource (a magnetron 37 in this embodiment), the application ofmicrowaves from the source can be moderated in response to the pressuredetected by the pressure sensor 108, or can be moderated by the coolingsystem in response to the temperature measured by the temperaturedetector 103 (FIGS. 10-11).

FIG. 2 also shows some additional details of the illustrated instrument.These include a stirrer motor 50 and its corresponding belt 51 which canbe used if desired to operate a magnetic stirrer bar (not shown) insidethe cavity 23. FIG. 2 also shows a plurality of brackets 52 that helpmount the cavity within the device, along with the posts 53 that areused to mount the magnetron 37 to the waveguide 40. These are basicstructural features and although included in FIG. 2 for the sake ofcompleteness, do not limit the scope of the invention or the claims. Anadditional bracket and screw are indicated together at 54. FIG. 2 alsoshows an additional set of cables 55 and plugs 56 for providingcommunication between the solenoid 43 and the processor. In a similarmanner, the post 57 is included in this particular embodiment to providea place where the housing of the instrument can be fixed to the portionsillustrated in FIG. 2.

FIG. 3 is a cross-sectional view taken along the axis of the attenuator31 and the cavity 23. A number of common elements from FIG. 2 areillustrated including the attenuator 31, the nut 33, the handles 41, andthe cavity 23. In particular, FIG. 3 helps illustrate the advantages ofthe instrument in using the attenuator 31 to position the flow cell, nowbroadly designated at 60, at a consistent position within the cavity 23as the attenuator 31 is releasably removed and re-engaged. FIG. 3illustrates that the flow cell 60 includes a number of structuralelements with one of the posts for this purpose being designated at 61in FIG. 3. In preferred embodiments, (FIG. 5), the structure of the cellincludes several of the posts 61, a bottom plate 62, and a top plate 63.The top plate 63 is illustrated somewhat more clearly in FIG. 4 andincludes a plurality of openings 64 between the posts 61.

In order to handle the fluid reactants, the flow cell 60 includes anextended length of tubing 65. The tubing 65 is illustrated in a “woven”pattern in FIGS. 3, 6, 7 and 8, or alternatively, in FIG. 3 in a morecontiguous wrapping pattern as shown on the left hand side of thecross-sectional view of FIG. 3. Although the particular pattern is notcrucial to the present invention, it will be understood that aconsistent pattern for the tubing is similarly expected to give the mostconsistent results with respect to the operation of the cavity and thus,to the running of particular reactions. The tubing 65 can be made of anymaterial that avoids interfering with the microwave field in the cavityand that is compatible with the starting materials, solvents, reagents,and expected products or byproducts. In preferred embodiments, thetubing is formed of a fluorocarbon polymer such as one of the variousTEFLON™ polymers, and is wrapped in a covering (wound, woven, orbraided) of fibers formed from an engineering polymer such as one of theKEVLAR® polyimides.

In order to provide the consistent positioning, the attenuator 31 isreleasably engaged with the cavity 23, and the flow cell 60 and itstubing 65 are releasably engaged with the attenuator 31 in a manner thatfixes the positions of the attenuator 31 and the flow cell 60 withrespect to one another when they are engaged and that correspondinglyfixes the flow cell 60 in the same position with respect to the cavity23 when the attenuator 31 is engaged with the cavity 23. Stateddifferently, the instrument permits the flow cell 60 to be placed in adesired fixed position in the cavity 23.

In the illustrated embodiment, the positioning is accomplished with theuse of a two-part (66, 67). The lower portion of the post 66 isthreadedly engaged with the top plate 63 of the flow cell 60 to define astandard position, while the top portion of the post 67 is likewisethreaded into the top plate 63 of the flow cell and maintained in placein the attenuator by the nut 33, previously described positioned on thetop exterior surface of the attenuator 31. In the illustratedembodiment, the post portions 66 and 67 serve an axillary function inthat they include respective coaxial openings (70 in post portion 66 and71 in post portion 67). These coaxially aligned shafts 70 and 71 providea thermal well into which an appropriate temperature measuring devicecan be positioned in order to measure temperature inside the cavity. Theincorporation of the thermal well is not, however, necessary for theother structural aspects of the post portions 66 and 67 and the thermalwell can be positioned elsewhere or the temperature measuring device canbe positioned elsewhere as may be desirable or necessary.

The temperature measuring device is preferably selected to be asminimally intrusive as possible. Suitable temperature measuring devicesinclude fiberoptic temperature sensors and transducers based on thethermal expansion of glass materials, of which representative commercialdevices are available from FISO Technologies, Inc. of Quebec, Canada.Such devices offer particular advantages because they avoid interferingwith, and are not affected by, microwave or radio frequency radiation.Alternatively, fiberoptic based infrared detecting thermometers such asthose commercially available from LUXTRON of Santa Clara, Calif. aresimilarly useful. These devices direct infrared frequencies emitted by awarm sample to an appropriate photodetector via optical fibers, with thephotodetector converting the measured wavelengths into a usefultemperature reading.

It will also be understood that the posts 66 and 67 can be used toadjust or change the position of the tubing 65 with respect to theattenuator 31 and thus with respect to the cavity 23. It will also beunderstood that the illustrated structure of the flow cell 60 and thepattern of the tubing 65 are exemplary, rather than limiting, of thepresent invention.

Other details illustrated in FIG. 3 and the embodiment it representsincludes the air inlet 72 which is incorporated with the drain pipe 73.During normal operation, air from the source, solenoid and regulatordescribed earlier, are directed into the cavity 23 through the air inlet72 and the drain pipe 73. The drain pipe 73 serves an additionalpurpose, however, in that if fluid spills or leaks in the cavity 23, thedrain pipe provides an available path to an appropriate spill tray. Theelbow 74 illustrated in cross-section in FIG. 3 is another portion ofthis draining system with the drain pan not being illustrated in FIG. 3.A bracket 75 holds several of these elements in place as desired ornecessary. Several of these features are also discussed in detail in thecorresponding incorporated applications.

FIG. 3 also illustrates the presence of a dielectric insert 76 (e.g.,formed of PTFE) which helps protect the interior of the cavity 23 andprovides are additional cooling path as set forth in the incorporatedapplications. The remaining portions illustrated in FIG. 3, particularlythe engagement between the cavity 23 and the attenuator 31 are bestunderstood with respect to other figures.

FIGS. 4 and 5 illustrate more aspects and details of the attenuator andflow cell and their relationship to the cavity 23. FIG. 4 is a partiallyexploded view illustrating the attenuator 31 and portions of the flowcell 60 exploded from the cavity 23. For the sake of clarity, several ofthe posts 61 are eliminated from FIG. 4. In order to provide aphysically and microwave secure engagement when the cavity andattenuator are engaged, the attenuator 31 is centered in a collar 80that includes at least two radially extending locking tabs 81 (only oneof which is visible in FIG. 4). The tabs 81 fit into correspondingreceiving openings 83 in upper portions of the cavity 23. In order toengage the attenuator 31 and its collar 80 with the cavity, the tabs 81are positioned in the tab receiving openings 83. Then to further securethe attenuator in place, the attenuator can be rotated approximately{fraction (1/4)} turn with the tabs 81 sliding in a locking channel 84adjacent and co-planar with the lower portions of the tab receivingopenings 83. As stated earlier, the handles 41 on the attenuator 31assist in turning the attenuator 31 to either engage it or disengage itwith the cavity 23. In preferred embodiments, the assembly includes themesh ring illustrated at 85 in FIG. 4 which helps with both themechanical and microwave sealing characteristics.

FIG. 4 also shows a few additional details such as several mountingscrews or rivets 86. Because the magnetron 37 is not illustrated in FIG.4, FIG. 4 also illustrates the opening 87 in the waveguide 40 into whichthe magnetron antenna (not shown) can extend to propagate the microwavesinto the waveguide 40 and then into the cavity 23.

FIG. 4 also illustrates an upper cover 90 for the attenuator 31 alongwith an upper collar 91. The cover or cap 90 covers the entire topopening of the attenuator, with the exception of the use of the post 67,and helps prevent heat loss through the attenuator 31.

FIG. 5 shows the attenuator 31 and cell 30 in exploded fashion apartfrom the cavity 23. All of the elements illustrated in FIG. 5 havealready been described and carry the same reference numerals as in theprevious drawings and description.

FIGS. 6 and 7 are perspective and side elevational views of theattenuator 31 and flow cell 60 engaged with one another. All of theelements illustrated in FIGS. 6 and 7 have already been describedpreviously and carry the same reference numerals as with respect to theother figures. Accordingly, FIGS. 6 and 7 provide an additional view andunderstanding of this aspect of the invention.

In the same manner, FIGS. 8 and 9 are cross-sectional views, takenperpendicularly to one another, of the assembled attenuator 31 and flowcell 60. FIG. 8 illustrates the nature in which the tubing 65 can beplaced around and between the posts 61 to define a flow path for fluidsthrough the flow cell 60.

FIG. 9 illustrates a number of the same elements, but with the upperpost 67 removed, and with the figure being in an orientation 90 degreesfrom that of FIG. 8. FIG. 9 perhaps most clearly shows the overall shapeof the attenuator 31 in a proposed preferred embodiment, including theu-shaped bottom portions 93. FIG. 9 also shows that the top plate 63 ofthe flow cell 60 defines a plurality of shafts 94 which permit themovement of air between the attenuator and the flow cell 60. Theremaining elements of FIG. 9 have similarly been described with respectto previous drawings and carry the same reference numerals.

FIGS. 10 and 11 help illustrate some of the functional relationships ofthe elements of the instrument and the method steps of the invention.FIGS. 9 and 10 are schematic diagrams, but wherever possible, commonreference numerals have been used with the other drawings.

Accordingly, FIG. 10 shows a source or vessel for reactants 97 which aredrawn by the pumping system 22, then preferably through a pressuretransducer 115, and delivered into the flow cell 60 in the cavity 23.From the flow cell 60 and the cavity 23, the reaction products, whichwill be understood to include desired products, byproducts, and in somecases unreacted starting materials, flow to and through the pressureregulator 108 following which they are scavenged in the scavenger 100.As set forth with respect to the method aspects of the claim, thescavenged products can then be immediately forwarded to a further stepwhich in FIG. 10 is illustrated as the high-pressure liquidchromatography, 101.

The pressure regulator 108 helps maintain a constant or near-constantpressure (250 psi is typical) in the fluid so that pressure fluctuationsdetected by the transducer 115 can be used by the processor 104 to helpmoderate conditions in the cavity. The pressure regulator (“backpressureregulator”) is a standard commercial device, with those available fromUpchurch Scientific (Oak Harbor, Wash.) being exemplary. Thebackpressure regulator offers several advantages, including moderatingthe pressure fluctuations that can occur when gas bubbles form in theflowing fluid, and serving as a pump preload for low pressureapplications.

FIG. 10 also schematically illustrates another microwave cavity 109(dotted lines). In this regard, the scavenging step is preferablycarried out under microwave irradiation either in the original cavity 23or in a separate cavity as indicated at 109. In both cases, the use ofmicrowaves greatly accelerates the rate of scavenging, and two specificcomparative examples are included later herein.

In FIGS. 10 and 11, the cooling system is designated at 102, thetemperature detector at 103, and the processor at 104. In FIG. 10 theprocessor is in signal communication with the cooling system 102 throughthe cable 105. It will be understood that a cable or wire is a presentlypreferred embodiment of the invention, but that any appropriate signalcommunication between the processor and the cooling system can beincorporated. These could include infrared communication as is commonwith certain computers and their peripheral devices, or communicationover some other assigned frequency within the electromagnetic spectrum,or an optical cabling system as the case may be. The processor is alsoin signal communication with the temperature detector 103 through thecable 106 and with the pressure detector (transducer) 115 through thecable 107, and with the source 37 through the cable 116.

FIG. 11 shows a number of the same elements as FIG. 10, but inparticular illustrates the spectroscopy cell 110 which is positionedexternal to the cavity 23 and in fluid communication with the outputside of the flow cell 60. A spectrometer represented by the source 111and detector 112 has the spectroscopy cell 110 in its optical path foranalyzing the characteristics of the fluid flowing from the flow cell 60and through the spectroscopy cell 110. The general principles andoperation of spectroscopy and spectrometers are well understand in thisand many related arts and will not be discussed in detail herein. Theterm “optical path” refers, of course, to the path defined between thesource 111 and the detector 112 and does not necessarily refer to thepassage of light within the visible spectrum. Indeed, as noted above, inaddition to potentially using visible light spectroscopy, the inventionmore preferably incorporates ultraviolet spectroscopy, infraredspectroscopy, Raman spectroscopy, each which operates in frequencies andwavelengths that are outside of the visible spectrum. As in the case ofFIG. 10, the processor 104 is in signal communication with the coolingsystem 102 through the cable 105. The processor 104 is in signalcommunication with the source 37 through the cable 116, with thetemperature detector 103 through the cable 106, and in signalcommunication with the spectrometer and its detector 112 through thecable 113.

The spectroscopic evaluating step preferably comprises at least portionsof the infrared spectrum of the fluid, or at least portions of theultraviolet spectrum of the cooling fluid, or at least portions of theRaman spectrum of the flowing fluid. In each case, it will be understoodthat when certain reactions are being carried out, certain portions oftheir spectrum are well understood and can be predictably identified aspresent or absent. Accordingly, the spectroscopic evaluation can, butdoes not require, a full selection of wavelengths. It can be limited asdesired or necessary to a relatively smaller range or set of ranges fromwhich the expected products, byproducts and remaining starting materialscan be identified.

With the processor and the signal communication in place, FIG. 10illustrates how the conditions in the cavity, particularly including theoperation of the microwave source 37 and the cooling system 102 can bemoderated in response to the pressure detector 115 or the temperaturedetector 103.

The term “processor” is used herein in its generally accepted sense, andsuch devices are also typically referred to as microprocessors,coprocessors, or CPUs (central processing unit). Downing, Dictionary ofComputer and Internet Terms, Sixth Ed. (1998), Barron's EducationalSeries, Inc., e.g., at pages 110, 293, and 370. As set forth therein,the processor carries out arithmetic and logical operations, and decodesand executes instructions. Processors useful for the operationsdescribed herein are commercially available, and in many casescorrespond to the processors incorporated in personal computers. Suchprocessors can also be programmed to carry out the operations describedherein by those of ordinary skill in the relevant arts and without undueexperimentation.

In an analogous manner, FIG. 11 illustrates how the processor 104 andits relationships can moderate the conditions in the cavity 23 bymoderating the microwave power from the source 37 or the operation ofthe cooling system 102 and in particular in response to the temperature103 or most preferably in response to the spectrometer and particularlythe detector 112.

EXPERIMENTAL

Tables 1-7 show some of the results of various experiments carried outusing the method and apparatus of the invention, and with comparisons toprior techniques in some cases.

Tables 1 and 2 are examples of scavenging carried out under theapplication of microwave radiation. In the experiments carried out inTables 1 and 2, acetonitrile was used as the solvent for the five listedcompounds. These compounds were selected as having those functionalgroups that amine-type scavengers are designed to remove. Accordingly,Table 1 represents a scavenging reaction carried out using asilica-based amine-3 scavenger from SiliCycle Inc. (Quebec City,Canada). As the results in Table 1 show, under the influence ofmicrowaves for four minutes, almost all of the compounds were entirelyscavenged. By way of comparison, under room temperature stirringconditions—i.e., a conventional scavenging technique—only three of thecompounds were removed.

For the scavenging of benzoyl chloride with amine-3 scavenger, 400 mg ofbenzoyl chloride were used in 1 ml of solvent (acetonitrile) to form a0.14M solution. Therefore 0.57 mmol of amine functional groupconstitutes 1 equivalent of scavenger. Four (4) equivalents would be 2.3mmol of scavenger, which is 158 mg for a loading capacity of 3.6 mmol/g.The benzoyl chloride, scavenger, and solvent are added together in a 10ml pressurized vessel and either put into the microwave system orstirred at room temperature The percent scavenged is determined byGC/MS. TABLE 1 % scavenged % scavenged Using acetonitrile microwave roomtemp Benzoyl chloride 100 100  Acetic Anhydride  99 99tert-butylphenylisocyanate 100 1,1,3,3-tetramethylbutylisocyanate 100benzaldehyde  97 97 Amine-3 Amine-3 4 EQ's, 4 EQ's, MW conditions rtconditions 4 min, 150 C., 300 W stirred 1 hr

Table 2 represents the same experiment carried out with the samecompounds, but using a triamine-3 silica based scavenger, and againcomparing a microwave technique versus a conventional technique. AsTable 2 indicates, microwave technique demonstrated equivalent orsuperior scavenging results in all cases, and was carried out in fourminutes rather than one hour. TABLE 2 % scavenged % scavenged Usingacetonitrile microwave room temp Benzoyl chloride 100  100  AceticAnhydride 97 99 tert-butylphenylisocyanate 95 621,1,3,3-tetramethylbutylisocyanate 89 62 benzaldehyde 80 59 Triamine-3Triamine-3 4 EQ's, 4 EQ's, MW conditions rt conditions 4 min, 150 C.,300 W Stirred 1 hr

Tables 3-7 are exemplary organic synthesis reactions carried out usingthe flow through techniques and apparatus of the present invention. Insome cases the results are shown in comparison to the identical reactioncarried out in batch fashion in a manner consistent with applicant'sco-pending 261 application. Unless indicated otherwise, the comparativebatch reactions were carried out in a DISCOVER™ instrument from CEMCorporation, Matthews, N.C. TABLE 3 Knoevenagel Invention DISCOVER ™Instrument 25 g malonic acid 0.098 g malonic acid 25 mL benzaldehyde0.096 ml benzaldehyde 35 mL pyridine 0.069 ml pyridine 15 mL ethanol 0.5ml EtOH FR = 1 ml/min 5 ml coil resonance time = 5 min 6 min ramp, 5 minhold Temp = 160 C. T = 175 C. P = 250 psi P = 250 psi Power = 300 W Pwr= 300 W Cooling = 1-2 psi Cooling = On Yield = 20%comparable result (U.S. Pat. No. 5,387,397): 18% yield

Table 3 shows the results of a Knoevenagel reaction (FIG. 12) using theindicated starting materials. In particular, a flow-through reaction wascarried out at a flow rate of 1 milliliter per minute in a 5-millilitercoil in an instrument according to the present invention, thus defininga residence time of 5 minutes. This was compared to a batch reactionamong the same compositions similarly carried out under microwaveirradiation for five minutes. As Table 3 indicates, the temperature andpowers used were equivalent and in the case of the invention, produced ayield of 20%, which is comparable to the results demonstrated in theprior art; e.g. U.S. Pat. No. TABLE 4 Esterification Invention 9.1 gbenzoic acid 30 mL MeOH 0.5 mL H2SO4 FR = 1.5 ml/min 5 ml coil residencetime = 3:20 Temp = 80 C. P = 250 psi Power = 75 W Cooling =15 psi Yield= 100%comparable result: 92% yield (U.S. Pat. No. 5,387,397)

Table 4 shows the results of an esterification reaction (FIG. 13)between benzoic acid and butanol in the presence of sulfuric acid. Theflow rate was set for 1.5 milliliter per minute in the 5-milliliter coilfor a residence time of 3 minutes and 20 seconds. Using the cooling ofthe present invention, the temperature could be maintained at 80°centigrade while the power was maintained at 75 watts to give a yield of100%. A comparable result from the prior art showed a 92% yield; e.g.U.S. Pat. No. TABLE 5 Transesterification Invention DISCOVER ™Instrument 30 mL BuOH 0.4 mL H2SO4 FR = 2 ml/min 5 ml coil Temp = 80 C.P = 250 psi Power = 100 W Cooling = 1-2 psi Yield = 89%comparable results (No. 5,387,397)40% - 1st pass48% - 2nd pass

Table 5 shows the results for a transesterification reaction (FIG. 14)between methyl-4-chlorodenzoate and butanol also in the presence ofsulfuric acid. The flow rate was 2 milliliter per minute in a5-milliliter core for a residence time of 2½ minutes. Once again, thecooling step of the present invention enabled the temperature to bemaintained at 80° C. while the power was applied at 100 watts. Thisproduced an 89% yield of product comparable to yields of 40 and 48% inthe prior art. TABLE 6 Nucleophilic Aromatic Substitution InventionDISCOVER ™ Instrument 6 g 4- 0.1 g 4-chlorobenzaldehydechlorobenzaldehyde 4.4 mL isopropyl amine 0.073 mL isopropyl amine 30 mLacetonitrile neat FR = 1.5 ml/min 5 ml coil residence time = 3:20 5 minramp, 10 min hold Temp = 90 C. Temp = 175 C. P = 250 psi P = 250 psiPower = 300 W Power = 100 W to 300 W Cooling = 10-13 psi Cooling = OnYield = 100% Yield = 100%

Table 6 shows a nucleophilic aromatic substitution reaction (FIG. 15).Table 6 demonstrates the comparison between the flow through techniqueof the present invention and the batch technique of the '261 applicationusing the DISCOVER™ instrument. In Table 6, the reaction times differedslightly in that the method of the invention was carried out at a1.5-milliliter flow rate in a 5-milliliter coil to produce a residencetime of 3 minutes and 20 seconds, while in the batch reaction thereaction was allowed to run for 10 minutes. In each case, proactivecooling was applied so that the power level could be maintained between100 and 300 watts. In each case, the yield was 100%. TABLE 7 Diels-AlderInvention DISCOVER ™ Instrument 6.8 mL furan .107 mL furan 15 mLdiethylacetylene .24 mL diethylacetylene dicarboxylate dicarboxylateneat Neat FR = 0.5 ml/min 5 ml coil residence time = 10:00 10 min holdTemp = 100 C. Temp = 100 C. P = 250 psi P = 200 psi Power = 300 W Power= 300 W Cooling 6-8 psi Cooling = On Yield = 92% Yield = 85%

Table 7 shows the results of a Diels-Alder reaction (FIG. 16) and againcomparing the flow through method of the present invention with thebatch technique of the 261 application. In each case, the residence timewas 10 minutes, with cooling applied to keep the temperature at 100° C.,thus allowing power of 300 watts to be applied. The flow throughtechnique of the invention showed a slightly greater yield of 92% ascompared to the batch yield of 85%.

In the drawings and specification there has been set forth a preferredembodiment of the invention, and although specific terms have beenemployed, they are used in a generic and descriptive sense only and notfor purposes of limitation, the scope of the invention being defined inthe claims.

1. A method of microwave assisted chemistry comprising: directing acontinuous flow of fluid through a microwave cavity while applyingmicrowave radiation to the cavity and to the continuous flow ofmaterials therein; monitoring the pressure of the fluid in the cavity;and cooling the fluid in the cavity when the pressure exceeds apredetermined setpoint pressure.
 2. A method according to claim 1wherein the cooling step comprises moderating the degree of cooling inresponse to the monitored pressure.
 3. A method according to claim 1wherein the step of cooling the fluid in the cavity comprisescirculating a coolant in the cavity in response to the pressure setpointdetermination.
 4. A method according to claim 3 comprising circulatingair as the coolant in the cavity.
 5. A method according to claim 1comprising directing the continuous flow of fluid through a single modemicrowave cavity.
 6. A method according to claim 1 wherein the step ofdirecting the fluid comprises directing the fluid in the presence of acatalyst.
 7. A method according to claim 1 wherein the step of directingthe fluid comprises directing the fluid in the presence of a scavengingcomposition.
 8. A method according to claim 1 wherein the steps ofmonitoring and cooling comprise: sending a signal representative of thepressure from a pressure monitor to a processor; using the processor tocompare the monitored pressure to the setpoint pressure; and sending asignal from the processor that initiates and runs a cavity coolingdevice whenever the monitored pressure exceeds the setpoint pressure. 9.A method according to claim 1 wherein the steps of directing and coolingthe fluid comprise: directing the fluid through a tube; and externallycooling the tube.
 10. A method according to claim 9 wherein the step ofexternally cooling the tube comprises directing a cooling fluid over theexterior of the tube.
 11. A method of microwave assisted chemistrycomprising carrying out a chemical reaction in batch format whileirradiating the reactants with microwave radiation and whileconcurrently externally cooling the reaction vessel to thereby identifyan optimum power level for the reaction and without exceeding atemperature at which the reactants decompose; thereafter directing acontinuous flow of corresponding reactants through a single modemicrowave cavity while applying microwave radiation to the cavity and tothe continuous flow of materials therein at the power level identifiedduring batch format reaction of the same reactants; and externallycooling the flowing reactants while applying the microwave radiation inorder to continue at the identified power level while avoiding anundesired increase in the temperature of the reaction.
 12. A method ofmicrowave assisted chemistry comprising: directing a continuous flow offluid that includes reactants through a single mode microwave cavitywhile applying microwave radiation to the cavity and to the continuousflow of materials therein; and purifying the reaction products with ascavenging composition in a single-mode microwave cavity.
 13. A methodaccording to claim 1 wherein the scavenging step comprises directing thefluid through a column filled with a solid support that includes ascavenging functional group selected from the group consisting ofelectrophilic scavengers, nucleophilic scavengers, and combinationsthereof.
 14. A method according to claim 12 and further comprising:monitoring the pressure of the fluid in the cavity; and cooling thefluid in the cavity when the pressure exceeds a predetermined setpoint.15. A method according to claim 12 and further comprising: monitoringthe pressure of the fluid in the cavity; and moderating the appliedmicrowave power when the pressure exceeds a predetermined setpoint. 16.A method according to claim 12 and further comprising: monitoring thetemperature in the cavity; and cooling the fluid in the cavity when thetemperature exceeds a predetermined setpoint.
 17. A method according toclaim 12 and further comprising: monitoring the temperature in thecavity; and moderating the applied microwave power when the temperatureexceeds a predetermined setpoint.
 18. A method according to claim 12 andfurther comprising immediately directing the purified reaction productsto a separation step.
 19. A method according to claim 18 wherein theseparation step comprises chromatography.
 20. A method according toclaim 19 wherein the chromatography step comprises high pressure liquidchromatography.
 21. An instrument for microwave assisted chemistrycomprising: a microwave cavity; a flow cell in said cavity; a pump fordirecting fluid reactants from at least one source to said flow cell; apressure meter in fluid communication with said flow cell for measuringthe pressure of fluid in said flow cell; and a cooling system forcooling said flow cell in said cavity.
 22. A microwave instrumentaccording to claim 21 and further comprising: a processor incommunication with said pressure meter and said cooling system formoderating the cooling of said flow cell in said cavity in response tothe pressure measured by said pressure meter.
 23. A microwave instrumentaccording to claim 22 and further comprising: a microwave source incommunication with said cavity and wherein said processor is incommunication with said source for moderating the application ofmicrowaves from the source in response to the pressure detected by saidpressure meter.
 24. A microwave instrument according to claim 23 andfurther comprising a temperature detector in said cavity and incommunication with said processor for moderating the application ofmicrowaves from said source or moderating the cooling of said flow cellby said cooling system in response to the temperature measured by saiddetector.
 25. A microwave instrument according to claim 21 comprising asingle mode cavity.
 26. A microwave instrument according to claim 21wherein said flow cell comprises: a microwave-transparent supportstructure; and microwave transparent tubing on said support structure.27. A microwave instrument according to claim 21 comprising a scavengingcell in said cavity.